Brain structural abnormalities in psychotropic drug-naive pediatric patients with obsessive-compulsive disorder

OBJECTIVE: The authors investigated structural abnormalities in brain regions comprising cortical-striatal-thalamic-cortical loops in pediatric patients with obsessive-compulsive disorder (OCD). METHOD: Volumes of the caudate nucleus, putamen, and globus pallidus and gray and white matter volumes of the anterior cingulate gyrus and superior frontal gyrus were computed from contiguous 1.5-mm magnetic resonance images from 23 psychotropic drug-naive pediatric patients with OCD (seven male patients and 16 female patients) and 27 healthy volunteers (12 male subjects and 15 female subjects). RESULTS: Patients had smaller globus pallidus volumes than healthy volunteers, but the two groups did not differ in volumes of the caudate nucleus, putamen, or frontal white matter regions. Compared to healthy volunteers, patients had more total gray matter in the anterior cingulate gyrus but not the superior frontal gyrus. Total anterior cingulate gyrus volume correlated significantly and positively with globus pallidus volume in the healthy volunteers but not in patients. CONCLUSIONS: These findings provide evidence of smaller globus pallidus volume in patients with OCD without the potentially confounding effects of prior psychotropic drug exposure. Volumetric abnormalities in the anterior cingulate gyrus appear specific to the gray matter in OCD, at least at the gross anatomic level, and are consistent with findings of functional neuroimaging studies that have reported anterior cingulate hypermetabolism in the disorder.     

The regional cerebral blood flow changes in major depressive disorder with and without psychotic features

Depressive patients with psychotic features demonstrate distinct biological abnormalities in the hypothalamic-pituitary-adrenal axis (HPA), dopaminergic activity, electroencephalogram sleep profiles and measures of serotonergic function when compared to nonpsychotic depressive patients. However, very few functional neuroimaging studies were specifically designed for studying the effects of psychotic features on neuroimaging findings in depressed patients. The objective of the present study was to compare brain Single Photon Emission Tomography (SPECT) images in a group of unmedicated depressive patients with and without psychotic features. Twenty-eight patients who fully met DSM-IV criteria for major depressive disorder (MDD, 12 had psychotic features) were included in the study. They were compared with 16 control subjects matched for age, gender and education. Both psychotic and nonpsychotic depressed patients showed significantly lower regional cerebral blood flow (rCBF) values in the left and right superior frontal cortex, and left anterior cingulate cortex compared to those of controls. In comparison with depressive patients without psychotic features (DwoPF), depressive patients with psychotic features (DwPF) showed significantly lower rCBF perfusion ratios in left parietal cortex, left cerebellum but had higher rCBF perfusion ratio in the left inferior frontal cortex and caudate nucleus. The present study showed that DwPF have a different rCBF pattern compared to patients without psychotic features. Abnormalities involving inferior frontal cortex, striatum and cerebellum may play an important role in the generation of psychotic symptoms in depression.     

Elevated thalamic and prefrontal regional cerebral blood flow in obsessive-compulsive disorder: a SPECT study

Functional neuroimaging studies have pointed to a possible role of cerebral circuits involving the prefrontal and anterior cingulate cortices, the striatum, and thalamus in the pathophysiology of obsessive-compulsive disorder (OCD). Regional cerebral blood flow (rCBF) of 16 drug-free Brazilian patients with OCD and 17 healthy subjects matched for age, gender, handedness and level of education was measured with [99m-Tc] HMPAO single photon emission computed tomography. Analysis of covariance identified four regions of interest with significantly higher rCBF: the right superior and inferior frontal cortex and the right and left thalamus. Positive correlations between symptom severity measured by Clinical Global Impression scores and rCBF were found in the right and left inferior frontal lobes and in the right basal ganglia. Compulsive behavior was inversely correlated with rCBF in the right thalamus, and duration of illness correlated positively with rCBF in the right and left superior frontal lobes and with the right thalamus. The findings of this SPECT study conducted in Brazil are in agreement with prior studies and provide additional support for the involvement of prefrontal-subcortical circuits in the pathophysiology of OCD. Furthermore, the study suggests that similar brain mechanisms appear to be involved cross-culturally.     

Caudate regional cerebral blood flow in obsessive-compulsive disorder, panic disorder and healthy controls on single photon emission computerised tomography

We compared regional cerebral blood flow (rCBF) in 15 patients with DSM IIIR obsessive-compulsive disorder (OCD), 15 patients with DSM IIIR panic disorder and 15 healthy controls matched for age, sex and hand preference, using uptake of technetium-99m-D,L-hexamethyl-propylene amine oxime (99mTc HMPAO), on single photon emission computerised tomography (SPECT). Caudate rCBF was significantly reduced in OCD patients compared to healthy subjects and panic disorder patients. When four patients were excluded from each group, right caudate rCBF remained significantly lower in OCD patients than in panic disorder patients or healthy subjects. The data suggest functional involvement of the right caudate nucleus is present in OCD.     

A voxel-based investigation of regional cerebral blood flow abnormalities in obsessive-compulsive disorder using single photon emission computed tomography (SPECT)

Several functional imaging studies have reported abnormalities of the orbitofrontal and anterior cingulate cortices, striatum and thalamus in obsessive-compulsive disorder (OCD). These studies have often been limited by small patient samples and image analysis methods that rely on region-of-interest (ROI) approaches. We have assessed resting regional cerebral blood flow with 99mTc-ECD SPECT in 26 unmedicated OCD patients and 22 healthy control subjects using the voxel-based Statistical Parametric Mapping method for data analysis. We found a significantly reduced ECD uptake in OCD patients relative to the control subjects in the right lateral orbitofrontal cortex, and in the left dorsal anterior cingulate cortex (P<0.001 two-tailed, uncorrected for multiple comparisons). There were significant positive correlations in the OCD group between the ECD uptake in the left lateral orbitofrontal cortex and ratings for obsessive-compulsive symptoms (OCS), and between the ECD uptake in the right medial orbitofrontal cortex and the ratings for both OCS and depressive symptoms. There were also unpredicted significant ECD uptake increases in the cerebellum in OCD patients, as well as a negative correlation between posterior cingulate ECD uptake and OCS severity (P<0.05, corrected for multiple testing). These results implicate specific subregions of the orbitofrontal and anterior cingulate cortices in the pathophysiology of OCD, as well as suggesting the involvement of other areas not usually included in ROI-based imaging studies. With the incorporation of voxel-based methods and the use of large patient samples, rCBF-SPECT studies may continue to provide valuable information about the functional anatomy of OCD.     

强迫症与抑郁症的脑单光子发射计算机断层扫描对照研究

目的探讨强迫症、抑郁症局部脑血流量(rCBF)特点。方法应用单光子发射计算机断层扫描(SPECT)技术,对首发且未经治疗的39例强迫症患者、36例抑郁症患者和39名正常人于静息状态下行脑血流显像。以小脑皮质的放射性计数值为参考,对局部脑血流进行半定量分析。结果强迫症组两侧前额叶、前颞叶rCBF高于正常组(P<0.01);抑郁症组两侧前额叶、枕叶、扣带回及右前颞叶、右顶叶rCBF低于正常组(P<0.05);在两侧前额叶、前颞叶、顶叶、枕叶及右后额叶、扣带回,强迫症组rCBF高于抑郁症组(P<0.05)。结论强迫症组的前额叶及前颞叶呈高灌注改变,抑郁症组脑血流普遍低灌注,SPECT技术可望作为二者鉴别诊断的客观依据之一。     

Neural correlates of clinical symptoms and cognitive dysfunctions in obsessive-compulsive disorder

Although results from neuropsychological and neuroimaging studies have postulated the involvement of the frontal lobe and the subcortical brain regions in the pathophysiology of obsessive-compulsive disorder (OCD), neuroimaging studies have provided little evidence that cognitive abnormalities in patients with OCD are related to dysfunctions in these areas. This study was designed to determine whether the clinical features and cognitive deficits of OCD might be taken to reflect frontal-subcortical dysfunction. Fourteen patients with OCD and 14 case-matched normal subjects completed clinical and cognitive evaluation, including four sets of neuropsychological tests that assessed the executive functions and visual memory. Cerebral glucose metabolic rates were measured by using positron emission tomography (PET) with 18F-fluorodeoxyglucose. Behavioral and PET data were analyzed using statistical parametric mapping for group differences and behavioral-metabolic correlates. The right orbitofrontal cortex showed increased metabolic activity and the left parieto-occipital junction showed decreased metabolic activity in patients. Metabolism in the right hippocampus, the left putamen and the right parietal region was associated with the severity of obsessive-compulsive symptoms. Correlations between metabolic rates and neuropsychological test scores in the prefrontal cortex and the putamen occurred only in the patient group. These results suggest that patients with OCD have distinct features of brain metabolic activities for performing cognitive tasks as well as presenting obsessive-compulsive symptoms. In particular, the frontal-subcortical circuits might mediate not only symptomatic expression but also cognitive expression in patients with OCD.     

Volumetric MRI study of key brain regions implicated in obsessive-compulsive disorder

Neuroanatomic abnormalities have been implicated in the pathophysiology of obsessive-compulsive disorder (OCD). To date, no study has measured the orbito-frontal cortex (OFC), anterior cingulate, caudate nucleus, and thalamus concurrently in first-episode patients. Thus, we performed a volumetric MRI study in patients who were treatment-naive and healthy controls focusing on the in vivo neuroanatomy of the whole brain, total gray and white matter volume, thalamus, caudate nucleus, anterior cingulate cortex, and OFC concurrently. The volumes of thalamus, caudate nucleus, anterior cingulate cortex, and OFC were measured in 12 OCD patients who were treatment-naive and 12 healthy control subjects. Anterior cingulate and OFC volumes included both white and gray matters. Volumetric measurements were made with T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5 T. The patients had increased white matter volume than healthy controls. The patient group had significantly smaller left and right OFC volumes and significantly greater left and right thalamus volumes compared with healthy controls. Anterior cingulate exhibited a near-significant difference between the patients and healthy controls on left side. Significant correlations were found between Y-BOCS scores and left OFC, and right OFC, and between Y-BOCS and left thalamus volumes in the patient group. In conclusion, our findings suggest that abnormalities in these areas may play an important role in the pathophysiology of OCD.     

Tc-99m HMPAO brain perfusion SPECT in drug-free obsessive-compulsive patients without depression

The aim of this study was to confirm prior results of brain-imaging studies on obsessive-compulsive disorder (OCD) in a sample of Turkish patients, as a cross-cultural study. Tc-99m HMPAO brain perfusion SPECT imaging was performed in nine drug-free OCD patients without depression and six controls. The patients' Hamilton Depression Rating Scale scores were <16. The severity of obsessive-compulsive symptoms was rated with the Yale-Brown Obsessive-Compulsive Rating Scale (YBOCS). Quantitative evaluation of regional cerebral blood flow revealed that right thalamus, left frontotemporal cortex and bilateral orbitofrontal cortex showed significant hyperperfusion in patients with OCD compared with controls. YBOCS scores did not show any correlation with hyperperfusion in regional cerebral blood flow in these areas. Results of this cross-cultural study may support orbitofrontal and thalamic dysfunction in OCD in a sample of Turkish patients.     

Effects of behavior therapy on regional cerebral blood flow in obsessive-compulsive disorder

Very few functional neuroimaging studies have been performed on patients with obsessive-compulsive disorder (OCD) undergoing behavior therapy, even though it is recognized to be an effective treatment for this disorder. We measured the regional cerebral blood flow (rCBF) using the Xenon inhalation method in 31 treatment-refractory patients with OCD and the same number of age-matched normal controls. We also studied changes in rCBF in 22 OCD patients who had demonstrated a significant improvement after the behavior therapy. The OCD patients showed a significant bilateral elevation in the rCBF in the basal ganglia compared with the normal controls. After successful treatment, a significant decrease was found in the rCBF in the right head of the caudate nucleus that tended to correlate with clinical improvement.     

Decreased thalamic blood flow in obsessive-compulsive disorder patients responding to fluvoxamine

Functional imaging studies have pointed to a role of the orbitofrontal cortex (OFC), striatum and thalamus in the pathophysiology of obsessive-compulsive disorder (OCD). Effective treatment has been found to change brain activity within this circuitry. The aim of the present study was to explore possible differential effects of OCD responders and non-responders to drug treatment on the regional cerebral blood flow (rCBF). Measurements of rCBF were carried out in 15 out of 22 patients with OCD who completed an open-label trial with fluvoxamine. Patients were studied with 99mTc-HMPAO single photon emission computed tomography (SPECT) before and after 12 weeks of treatment. In addition, structural magnetic resonance imaging was obtained on all patients. Regions of interest comprised the OFC, caudate nucleus, putamen and thalamus. Seven patients responded to treatment. Levels of rCBF decreased significantly in the left caudate nucleus and the left and right putamen in both responders and non-responders to treatment. In responders, but not in non-responders, a significant decrease in rCBF was found in the right thalamus. Pre-treatment cerebellar and whole brain HMPAO uptake was significantly higher in responders to treatment compared with non-responders. We suggest that the thalamus plays a central role in the response to drug treatment.     

Low level of dopaminergic D2 receptor binding in obsessive-compulsive disorder.

BACKGROUND: Despite growing evidence for involvement of the dopaminergic system in obsessive-compulsive disorder (OCD), the functional anatomy of the dopaminergic system in the basal ganglia has been investigated sparsely. METHODS: Dopamine D(2) receptor binding was assessed in 10 medication-free OCD patients and 10 healthy control subjects, matched for age, gender, and handedness. The binding potential was measured with single photon emission computerized tomography (SPECT) and infusion of the D(2) receptor radiotracer [(123)I] iodobenzamide. With magnetic resonance imaging as reference, regions of interest (caudate and putamen) were delineated for each hemisphere and coregistered with the corresponding SPECT scans. RESULTS: Dopamine D(2) receptor binding in the left caudate nucleus was significantly lower in the patients with OCD than in healthy control subjects [F(1,18) = 7.0, p =.016]. In addition, an interhemispheric difference was observed in the patient sample. Both the D(2) receptor binding potential (df = 9, p =.012), and the volume (df = 9, p =.029) of the left caudate nucleus were statistically significantly reduced relative to the right caudate nucleus. CONCLUSIONS: This study provides in vivo evidence for abnormalities in the binding potential of the dopamine D(2) receptor, which suggest the direct involvement of the dopaminergic system in the pathophysiology of OCD.     

Distinct neural correlates of washing, checking, and hoarding symptom dimensions in obsessive-compulsive disorder

CONTEXT: Obsessive-compulsive disorder (OCD) is clinically heterogeneous, yet most previous functional neuroimaging studies grouped together patients with mixed symptoms, thus potentially reducing the power and obscuring the findings of such studies. OBJECTIVE: To investigate the neural correlates of washing, checking, and hoarding symptom dimensions in OCD. DESIGN: Symptom provocation paradigm, functional magnetic resonance imaging, block design, and nonparametric brain mapping analyses. SETTING: University hospital. PARTICIPANTS: Sixteen patients with OCD (11 inpatients, 5 outpatients) with mixed symptoms and 17 healthy volunteers of both sexes.Intervention All subjects participated in 4 functional magnetic resonance imaging experiments. They were scanned while viewing alternating blocks of emotional (washing-related, checking-related, hoarding-related, or aversive, symptom-unrelated) and neutral pictures, and imagining scenarios related to the content of each picture type.Main Outcome Measure Blood oxygenation level-dependent response. RESULTS: Both patients and control subjects experienced increased subjective anxiety during symptom provocation (patients significantly more so) and activated neural regions previously linked to OCD. Analyses of covariance, controlling for depression, showed a distinct pattern of activation associated with each symptom dimension. Patients demonstrated significantly greater activation than controls in bilateral ventromedial prefrontal regions and right caudate nucleus (washing); putamen/globus pallidus, thalamus, and dorsal cortical areas (checking); left precentral gyrus and right orbitofrontal cortex (hoarding); and left occipitotemporal regions (aversive, symptom-unrelated). These results were further supported by correlation analyses within patients, which showed highly specific positive associations between subjective anxiety, questionnaire scores, and neural response in each experiment. There were no consistently significant differences between patients with (n = 9) and without (n = 7) comorbid diagnoses. CONCLUSIONS: The findings suggest that different obsessive-compulsive symptom dimensions are mediated by relatively distinct components of frontostriatothalamic circuits implicated in cognitive and emotion processing. Obsessive-compulsive disorder may be best conceptualized as a spectrum of multiple, potentially overlapping syndromes rather than a unitary nosologic entity.     

Local cerebral glucose metabolic rates in obsessive-compulsive disorder. Patients treated with clomipramine

In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessive-compulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.     

Cerebral activation in children and adolescents with obsessive-compulsive disorder before and after treatment: a functional MRI study

BACKGROUND: Structural and functional fronto-striatal abnormalities are involved in the pathophysiology of obsessive-compulsive disorder (OCD). The aims of the present study were: (a) to investigate possible regional brain dysfunction in premotor cortico-striatal activity in drug-na?ve children and adolescents with OCD; (b) to correlate brain activation with severity of obsessive-compulsive symptomatology; and (c) to detect possible changes in brain activity after pharmacological treatment. METHOD: Twelve children and adolescents (age range 7-18 years; seven male, five female) with DSM-IV obsessive-compulsive disorder and twelve healthy subjects matched for age, sex and intellectual level were studied. Functional magnetic resonance imaging data were obtained during the performance of simple and complex sequences. RESULTS: Comparing the complex motor condition with the simple control condition, both patients and controls showed a pattern of cerebral activation involving the fronto-parietal cortex and basal ganglia. Compared with controls, OCD patients presented significantly higher brain activation bilaterally in the middle frontal gyrus. After 6 months of pharmacological treatment and with clear clinical improvement, activation in the left insula and left putamen decreased significantly. CONCLUSION: In a paediatric OCD sample that was treatment na?ve and without another psychiatric disorder we showed hyperactivation of the circuits that mediate symptomatic expression of OCD. The cerebral activation decreases after treatment and clinical improvement.     

Neural mechanisms of decision making in hoarding disorder

CONTEXT Hoarding disorder (HD), previously considered a subtype of obsessive-compulsive disorder (OCD), has been proposed as a unique diagnostic entity in DSM-5. Current models of HD emphasize problems of decision-making, attachment to possessions, and poor insight, whereas previous neuroimaging studies have suggested abnormalities in frontal brain regions. OBJECTIVE To examine the neural mechanisms of impaired decision making in HD in patients with well-defined primary HD compared with patients with OCD and healthy control subjects (HCs). DESIGN We compared neural activity among patients with HD, patients with OCD, and HCs during decisions to keep or discard personal possessions and control possessions from November 9, 2006, to August 13, 2010. SETTING Private, not-for-profit hospital. PARTICIPANTS A total of 107 adults (43 with HD, 31 with OCD, and 33 HCs). MAIN OUTCOME MEASURES Neural activity as measured by functional magnetic resonance imaging in which actual real-time and binding decisions had to be made about whether to keep or discard possessions. RESULTS Compared with participants with OCD and HC, participants with HD exhibited abnormal activity in the anterior cingulate cortex and insula that was stimulus dependent. Specifically, when deciding about items that did not belong to them, patients with HD showed relatively lower activity in these brain regions. However, when deciding about items that belonged to them, these regions showed excessive functional magnetic resonance imaging signals compared with the other 2 groups. These differences in neural function correlated significantly with hoarding severity and self-ratings of indecisiveness and "not just right" feelings among patients with HD and were unattributable to OCD or depressive symptoms. CONCLUSIONS Findings suggest a biphasic abnormality in anterior cingulate cortex and insula function in patients with HD related to problems in identifying the emotional significance of a stimulus, generating appropriate emotional response, or regulating affective state during decision making.     

Elevated frontal cerebral blood flow in Gilles de la Tourette syndrome: a 99Tcm-HMPAO SPECT study.

Case reports, numerous brain imaging studies, and certain disease states suggest that the orbital frontal cortex and the striatum are dysfunctional in obsessive-compulsive disorder (OCD). Interest has also grown recently concerning the genetic, neuroanatomic, and clinical links between OCD, chronic motor tics, and Gilles de la Tourette Syndrome (GTS). To test the hypothesis of possible orbito-frontal/basal ganglia dysfunction in GTS, similar to OCD, we studied 20 unmedicated GTS subjects, 10 of whom also had comorbid OCD (GTS/OCD), and 8 control subjects. The subjects were examined with high-resolution single photon emission computed tomography (SPECT) and the labeled regional cerebral blood flow (rCBF) ligand technetium-99m-d,l-hexamethyl-propylene amine oxime (99Tcm-HMPAO). As a group, GTS subjects showed significantly elevated right frontal/visual cortex activity (mean = 0.879, SD = 0.107) compared with control subjects (mean = 0.798, SD = 0.049). A subanalysis comparing simple GTS versus GTS with comorbid OCD failed to reveal significant differences in regional flow.     

Greater regional cortical gray matter thickness in obsessive-compulsive disorder

Earlier studies are inconsistent regarding the structural basis of obsessive-compulsive disorder (OCD), and few studies have investigated whether patients with OCD have cortical thickness abnormalities compared with healthy volunteers. Using magnetic resonance imaging we compared regional differences in cortical thickness among 21 patients with OCD and 21 demographically matched healthy volunteers. Our findings indicate that the right inferior frontal cortex and posterior middle temporal gyrus are thicker in patients with OCD compared with healthy controls, which may contribute to response inhibition deficits and other aspects of phenomenology related to the disorder.     

Functional brain imaging in obsessive-compulsive disorder secondary to neurological lesions

Obsessive-compulsive disorder (OCD) may result from a range of neurological lesions in frontal and basal ganglia areas. However, relatively few studies have explored functional brain imaging in acquired OCD. METHODS: Charts of patients presenting to our Neuropsychiatry Unit where obsessive-compulsive symptoms appeared secondary to neurological lesions were reviewed. Demographic information and clinical diagnoses were collated, and brain SPECT scans reviewed. Six patients with various neurological conditions presented with OCD. All demonstrated decreased blood flow in the temporal lobes as well as cortical perfusion abnormalities in the frontal lobes (focal areas of decreased perfusion in one patient, focal areas of increased perfusion in two, and a combination of focal increased and decreased frontal perfusion in three cases). Abnormal blood flow may be seen in a number of different brain regions in acquired OCD. It is unclear whether these changes reflect primary neurological lesions or secondary changes to compensate for such damage. However, increased frontal blood flow in OCD may be hypothesized to reflect a compensatory mechanism.     

A functional MRI comparison of patients with obsessive-compulsive disorder and normal controls during a Chinese character Stroop task

Recent functional neuroimaging and neuropsychological studies have suggested that abnormal activity in the anterior cingulate cortex (ACC) might cause an action-monitoring dysfunction in obsessive-compulsive disorder (OCD). To identify the relationship between brain dysfunction and cognitive dysfunction, we examined regional brain changes in OCD with functional magnetic resonance imaging (fMRI) during the performance of a cognitive task. Participants comprised 24 patients with OCD and 14 normal controls. First, we compared the cognitive function in the two groups as assessed by several neuropsychological tests. Then we used fMRI to explore brain correlates of their performance during the Chinese character version of the Stroop test, a task that is strongly related to action-monitoring function. The two groups did not differ on the neuropsychological tests. Both groups also showed similar activation pattern on fMRI. The patients, however, showed weaker activation than the normal controls in the ACC and the right caudate nucleus.